Effects of PYY and PP on endocrine pancreas

Novel intestinal polypeptide YY (PYY) and pancreatic polypeptide (PP) were infused in fed anaesthetized rats. The peptides (10 and 100 pmol/kg · min) were administered during 30 min, alone, together with glucose or together with arginine. Plasma concentrations of glucose, insulin and glucagon were measured. At the dose of 10 pmol/kg · min the peptides had no effect. PP at the dose of 100 pmol/kg · min slightly augmented basal, but had no effect on stimulated insulin and glucagon release. PYY at the dose of 100 pmol/kg · min was without effect on basal insulin and glucagon levels and on glucose-induced insulin release, but exerted an inhibitory effect on arginine-induced secretion of both insulin and glucagon. It is unlikely that PYY and PP can affect secretion of insulin and glucagon via blood circulation. The potential capability of high doses of PP to affect insulin and glucagon secretion suggests that this peptide may exert direct (paracrine) effects on the pancreatic A-and B-cells     

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Neutrophils and neutrophil‐released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN‐λ1/IL‐29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST‐segment elevation myocardial infarction (STEMI), we show that IFN‐λ1/IL‐29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet–neutrophil interaction plays a major role in NET‐induced thromboinflammation, we further studied how IFN‐λ1/IL‐29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet‐derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN‐λ1/IL‐29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl₃‐induced arterial thrombosis that IFN‐λ2/IL‐28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN‐λ1/IL‐29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1–10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5–100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.     

Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells

HgCl2 is a known environemental neurotoxin, but is also used as preservative in vaccines as thimerosal containing ethyl mercury covalently linked to thiosalicylate. We recently reported that mercury choloride (HgCl(2)) can stimulate human mast cells to release vascular endothelial growth factor (VEGF), which is also vasoactive and pro-inflammatory. Here we show that thimerosal induces significant VEGF release from human leukemic cultured LAD2 mast cells (at 1 microM 326 ± 12 pg/106 cells and 335.5 ± 12 pg/106 cells at 10 microM) compared to control cells (242 ± 21 pg/106 cells, n=5, p less than 0.05); this effect is weaker than that induced by HgCl2 at 10 microM (448 ± 14 pg/106 cells) (n=3, p less than 0.05). In view of this finding, we hypothesize that the thiosalicylate component of thimerosal may have an inhibitory effect on VEGF release. Thimerosal (10 microM) added together with the peptide Substance P (SP) at 2 microM, used as a positive control, reduced VEGF release by 90 percent. Methyl thiosalicylate (1 or 10 microM) added with either SP or HgCl2 (10 microM) inhibited VEGF release by 100 percent, while sodium salicylate or ibuprofen had no effect. Pretreatment for 10 min with the flavonoid luteolin (0.1 mM) before HgCl2 or thimerosal compeletly blocked their effect. Luteolin and methyl thiosalicylate may be useful in preventing mercury-induced toxicity.     

Maternal health outcomes among HIV-infected breastfeeding women with high CD4 counts: results of a treatment strategy trial

Background: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery.

Methods: Women with pre-ART CD4+ cell counts ≥350 cells/mm³ who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat.

Findings: 1611 women were enrolled (June 2011–October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm³ and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p?=?0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p?=?0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p?=?0.61).

Interpretation: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.     

胺碘酮联合稳心颗粒治疗新发心房纤颤的临床体会

目的探讨胺碘酮联合稳心颗粒治疗新发心房纤颤的临床疗效。方法选取2010年4月—2014年3月于本院接受治疗的新发心房纤颤患者46例作为研究对象。将其分成对照组及观察组,各23例。对照组给予盐酸胺碘酮联合维拉帕米治疗;观察组给予胺碘酮及稳心颗粒的联合治疗。比较两组患者的临床疗效。结果观察组临床治疗的总有效率高于对照组,差异有统计学意义（P〈0.05）。结论胺碘酮联合稳心颗粒治疗新发心房纤颤,不仅临床治疗疗效显著,而且对患者的身体素质以及生存质量具有提升作用。     

MALIGNANT HISTIOCYTOSIS Histiocytic Medullary Reticulosis

ABSTRACT. Three cases of malignant histiocytosis occurring in children aged 2 months, 10 months and 14 years, are described. In all children the diagnosis was based on anaemia, granulocytopenia or thrombocytopenia, splenomegaly and marked erythrophagocytosis by bone marrow and lymph node atypical histiocytes. Two children aged 10 months and 14 years, underwent splenectomy after which combined chemotherapy with cyclophosphamide, vincristine and prednisone (COP) was started. In the older child a complete remission was achieved. The younger child died soon after the onset of the treatment. The youngest child was treated with bleomycin, adriamycin, cyclophosphamide, vincristine and prednisone (BACOP). He died of pneumonia and sepsis two months after the start of the treatment.     

Alkaline Phosphatase in the Developing Bursa of Fabricius

The ontogeny of alkaline phosphatase in the bursa of Fabricius was studied by histochemical and biochemical methods. According to the quantitative determinations, the activity of alkaline phosphatase increased from the 11th to 17th day of incubation--that is, during the time of the lymphoid follicle formation in the developing bursa. The activity was localized in the mesenchymal tissue surrounding the lymphoid follicles. Testosterone given in ovo prevented the appearance of alkaline phosphatase in the bursal mesenchyme but had no effect on the activity of the embryonic liver. In contrast, in ovo treatment with cyclophosphamide had no effect on the alkaline phosphatase in the bursa. By using transplantation of embryonic bursal stem cells, it was further shown that, in contrast to cyclophosphamide, testosterone destroys the capacity of the bursa to serve as a differentiation site for the B-cell lineage. The results indicate that testosterone affects the stromal cells of the bursa, whereas cyclophosphamide destroys only the lymphoid population undergoing differentiation and leaves the bursal stroma intact.     

Idiopathic spontaneous haemoperitoneum due to a ruptured middle colic artery aneurysm

Introduction

Idiopathic spontaneous intra-abdominal haemorrhage is a rare, but challenging condition, associated with high mortality if not managed appropriately. The preoperative diagnosis is difficult, despite the recent advances in imaging. We present the clinical manifestations of this condition, as well as the available diagnostic and therapeutic modalities.

Presentation of case

We report a case of a spontaneously ruptured dissecting aneurysm of the middle colic artery, which was managed with an emergency laparotomy and aneurysmatectomy. Interestingly, no evidence of vasculitis, infection or collagen disease was discovered during the histopathology examination of the specimen.

Discussion

The treatment of idiopathic spontaneous intra-abdominal haemorrhage revolves around patient resuscitation and management of the source of bleeding. In case of a ruptured aneurysm of the middle colic artery, the surgical management includes emergency laparotomy, arterial ligation and resection of the aneurysm. Transarterial embolisation has been suggested as a safe and less invasive alternative approach.

Conclusion

A ruptured middle colic artery aneurysm should be included in the differential diagnosis of any unexplained intra-abdominal haemorrhage. Aneurysmatectomy is the treatment of choice, with radiologic interventional techniques gaining ground in the management of this entity.